NOL4, known as nucleolar protein 4, has been implicated in multiple biological processes. It can interact with Mlr1 and Mlr2 (mouse homologs of transcription factor Mblk-1), and its splice variants differentially regulate the transactivation activities of Mlr1 and Mlr2, suggesting a role in transcriptional regulation [4,5]. Genome-wide association studies have associated NOL4 with age at menarche, indicating a potential role in sexual maturation [7].

In cancer research, NOL4 shows promise as a diagnostic and therapeutic target. In small cell lung cancer (SCLC), it is a nuclear marker with high specificity and positive predictive value, and is also an immunogenic antigen expressed specifically in SCLC, making it potentially useful for diagnosis and immunotherapy [1,3,6]. In papillary thyroid carcinoma, NOL4 is downregulated and hyper-methylated, suggesting it may act as a tumor suppressor gene [2]. In hepatocellular carcinoma, NOL4 is part of a six-gene CTA signature that serves as a prognostic predictor [8]. Additionally, in osteoclast differentiation, Nol4 knockout mice exhibit increased bone mineral density, indicating its relation to osteoclast activity [9].

In summary, NOL4 has diverse functions in transcriptional regulation, sexual maturation, and various disease contexts such as cancer and bone metabolism. Studies using gene knockout models, especially in the context of osteoclast activity, have provided insights into its role in biological processes. In cancer, NOL4 shows potential as a diagnostic, prognostic, and therapeutic target.

References:

1. Lee, Jung Hee, Shin, Dong Hoon, Lee, Sang Yull, Na, Joo Young, Kim, Jee Yeon. 2022. NOL4 is a novel nuclear marker of small cell carcinoma and other neuroendocrine neoplasms. In Histology and histopathology, 37, 1091-1098. doi:10.14670/HH-18-540. https://pubmed.ncbi.nlm.nih.gov/36282054/

2. Sheikholeslami, Sara, Azizi, Fereidoun, Ghasemi, Asghar, Hedayati, Mehdi, Teimoori-Toolabi, Ladan. 2020. NOL4 is Downregulated and Hyper-Methylated in Papillary Thyroid Carcinoma Suggesting Its Role as a Tumor Suppressor Gene. In International journal of endocrinology and metabolism, 18, e108510. doi:10.5812/ijem.108510. https://pubmed.ncbi.nlm.nih.gov/33613681/

3. Kim, Ye-Rin, Kim, Ki-Uk, Lee, Jung-Hee, Shin, Yong-Il, Lee, Sang-Yull. 2021. Cancer Testis Antigen, NOL4, Is an Immunogenic Antigen Specifically Expressed in Small-Cell Lung Cancer. In Current oncology (Toronto, Ont.), 28, 1927-1937. doi:10.3390/curroncol28030179. https://pubmed.ncbi.nlm.nih.gov/34065612/

4. Takayanagi-Kiya, Seika, Kiya, Taketoshi, Kunieda, Takekazu, Kubo, Takeo. 2017. Mblk-1 Transcription Factor Family: Its Roles in Various Animals and Regulation by NOL4 Splice Variants in Mammals. In International journal of molecular sciences, 18, . doi:10.3390/ijms18020246. https://pubmed.ncbi.nlm.nih.gov/28125049/

5. Takayanagi-Kiya, Seika, Misawa-Hojo, Kayo, Kiya, Taketoshi, Kunieda, Takekazu, Kubo, Takeo. . Splicing variants of NOL4 differentially regulate the transcription activity of Mlr1 and Mlr2 in cultured cells. In Zoological science, 31, 735-40. doi:10.2108/zs140049. https://pubmed.ncbi.nlm.nih.gov/25366156/

6. G, Pavithran, Rathi, Bhawna, Santoshi, Seneha. 2023. Translational and structural vaccinomics approach to design a multi-epitope vaccine against NOL4 autologous antigen of small cell lung cancer. In Immunologic research, 71, 909-928. doi:10.1007/s12026-023-09404-1. https://pubmed.ncbi.nlm.nih.gov/37410306/

7. Tsai, Meng-Che, Hsu, Chih-Hui, Chu, Shih-Kai, Roy-Gagnon, Marie-Hélène, Lin, Sheng-Hsiang. 2023. Genome-wide association study of age at menarche in the Taiwan Biobank suggests NOL4 as a novel associated gene. In Journal of human genetics, 68, 339-345. doi:10.1038/s10038-023-01124-6. https://pubmed.ncbi.nlm.nih.gov/36710296/

8. Xu, Yingyu, Xu, Xin, Ni, Xiaojian, Song, Guohe, Zhang, Juan. 2023. Gene-based cancer-testis antigens as prognostic indicators in hepatocellular carcinoma. In Heliyon, 9, e13269. doi:10.1016/j.heliyon.2023.e13269. https://pubmed.ncbi.nlm.nih.gov/36950598/

9. Toor, Salman M, Wani, Sachin, Albagha, Omar M E. 2021. Comprehensive Transcriptomic Profiling of Murine Osteoclast Differentiation Reveals Novel Differentially Expressed Genes and LncRNAs. In Frontiers in genetics, 12, 781272. doi:10.3389/fgene.2021.781272. https://pubmed.ncbi.nlm.nih.gov/34868271/